Neprilysin inhibitors

A compound of formula I:

• where:
• R1 is selected from —OR7 and —NR8R9;
• R2 is H or —P(O)(OH)2 or R2 is taken together with R7 to form —CR18R19— or is taken together with R8 to form —C(O)—;
• X is a —C1-9heteroaryl;
• R3 is absent or is selected from H;
• halo;
• —C0-5alkylene-OH;
• —NH2;
• —C1-6alkyl;
• —CF3;
• —C3-7cycloalkyl;
• —C0-2alkylene-O—C1-6alkyl;
• —C(O)R20;
• —C0-1alkylene-COOR21;
• —C(O)NR22R23;
• —NHC(O)R24;
• ═O;
• —NO2;
• —C(CH3)═N(OH);
• phenyl optionally substituted with one or two groups independently selected from halo, —OH, —CF3, —OCH3, —NHC(O)CH3, and phenyl;
• naphthalenyl;
• pyridinyl;
• pyrazinyl;
• pyrazole optionally substituted with methyl;
• thiophenyl optionally substituted with methyl or halo;
• furanyl;
• and —CH2-morpholinyl;
• and R3, when present, is attached to a carbon atom;
• R4 is absent or is selected from H;
• —OH;
• —C1-6alkyl;
• —C1-2alkylene-COOR35;
• —CH2OC(O)CH(R36)NH2;
• —OCH2OC(O)CH(R36)NH2;
• —OCH2OC(O)CH3;
• —CH2OP(O)(OH)2;
• —CH2CH(OH)CH2OH;
• —CH[CH(CH3)2]—NHC(O)O—C1-6alkyl;
• pyridinyl;
• and phenyl or benzyl optionally substituted with one or more groups selected from halo, —COOR35, —OCH3, —OCF3, and —SCF3;
• and R4, when present, is attached to a carbon or nitrogen atom;
• or R3 and R4 are taken together to form -phenylene-O—(CH2)1-3— or -phenylene-O—CH2—CHOH—CH2—;
• a is 0 or 1;
• R5 is selected from halo, —CH3, —CF3, and —CN;
• b is 0 or an integer from 1 to 3;
• each R6 is independently selected from halo, —OH, —CH3, —OCH3, and —CF3;
• R7 is selected from H, —C1-8alkyl, —C1-3alkylene-C6-10aryl, —C1-3alkylene-C1-9heteroaryl, —C3-7cycloalkyl, —[(CH2)2O]1-3CH3, —C1-6alkylene-OC(O)R10, —C1-6alkylene-NR12R13, —C1-6alkylene-C(O)R31, —C0-6alkylenemorpholinyl, —C1-6alkylene-SO2—C1-6alkyl,
• R10 is selected from —C1-6alkyl, —O—C1-6alkyl, —C3-7cycloalkyl, —O—C3-7cycloalkyl, phenyl, —O-phenyl, —NR12R13, —CH[CH(CH3)2]—NH2, —CH—NHC(O)O—C1-6alkyl, and —CH(NH2)CH2COOCH3;
• and R12 and R13 are independently selected from H, —C1-6alkyl, and benzyl;
• or R12 and R13 are taken together as —(CH2)3-6—, —C(O)—(CH2)3—, or —(CH2)2—O—(CH2)2—;
• and R31 is selected from —O—C1-6alkyl, —O-benzyl, and —NR12R13;
• R32 is —C1-6alkyl or —C0-6alkylene-C6-10aryl;
• R8 is selected from H, —OH, —OC(O)R14, —CH2COOH, —O-benzyl, pyridyl, and —OC(S)NR15R16;
• R14 is selected from H, —C1-6alkyl, —C6-10aryl, —OCH2—C6-10aryl, —CH2O—C6-10aryl, and —NR15R16;
• and R15 and R16 are independently selected from H and —C1-4-alkyl;
• R9 is selected from H, —C1-6alkyl, and —C(O)R17;
• and R17 is selected from H, —C1-6alkyl, —C3-7cycloalkyl, —C6-10aryl, and —C1-9heteroaryl;
• R18 and R19 are independently selected from H, —C1-6alkyl, and —O—C3-7cycloalkyl, or R18 and R19 are taken together to form ═O;
• R20 is selected from H and —C1-6alkyl;
• R21 and R35 are independently selected from H, —C1-6alkyl, —C1-3alkylene-C6-10aryl, —C1-3alkylene-C1-9heteroaryl, —C3-7cycloalkyl, —[(CH2)2O]1-3CH3, —C1-6alkylene-OC(O)R25, —C1-6alkylene-NR27R28, —C1-6alkylene-C(O)R33, —C0-6alkylenemorpholinyl, —C1-6alkylene-SO2—C1-6alkyl,
• R25 is selected from —C1-6alkyl, —O—C1-6alkyl, —C3-7cycloalkyl, —O—C3-7cycloalkyl, phenyl, —O-phenyl, —NR27R28, —CH—NH2, —CH[CH(CH3)2]—NHC(O)O—C1-6alkyl, and —CH(NH2)CH2COOCH3;
• R27 and R28 are independently selected from H, —C1-6alkyl, and benzyl;
• or R27 and R28 are taken together as —(CH2)3-6—, —C(O)—(CH2)3—, or —(CH2)2—O—(CH2)2—;
• R33 is selected from —O—C1-6alkyl, —O-benzyl, and —NR27R28;
• and R34 is —C1-6alkyl or —C0-6alkylene-C6-10aryl;
• R22 and R23 are independently selected from H, —C1-6alkyl, —CH2COOH, —(CH2)2OH, —(CH2)2OCH3, —(CH2)2SO2NH2, —(CH2)2N(CH3)2, —C0-1alkylene-C3-7cycloalkyl, and —(CH2)2-imidazolyl;
• or R22 and R23 are taken together to form a saturated or partially unsaturated —C3-5heterocycle optionally substituted with halo, —OH, —COOH, or —CONH2;
• and optionally containing an oxygen atom in the ring;
• R24 is selected from —C1-6alkyl;
• —C0-1alkylene-O—C1-6alkyl;
• phenyl optionally substituted with halo or —OCH3;
• and —C1-9heteroaryl;
• and
• R36 is selected from H, —CH(CH3)2, phenyl, and benzyl;
• where each alkyl group in R1, R3, and R4 is optionally substituted with 1 to 8 fluoro atoms;
• and;
• where the methylene linker on the biphenyl is optionally substituted with one or two —C1-6alkyl groups or cyclopropyl;
• or a pharmaceutically acceptable salt thereof.